RÉSUMÉ
BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors marked a milestone in the breast cancer treatment. Due to the potential impact of adverse effects on treatment decisions and patient outcomes, careful consideration of the varying toxicities of CDK4/6 inhibitors is crucial, as three inhibitors-palbociclib, abemaciclib, and ribociclib-have been approved with differences in adverse event profiles. However, limitations in clinical trials call for urgent real-world safety studies to evaluate and compare the risk of adverse events (AEs) among these CDK4/6 inhibitors. Therefore, this study aimed to analyze AEs of CDK4/6 inhibitors and provide insights for clinical drug selection, using real world database. METHODS: The AEs of CDK4/6 inhibitors in the FDA Adverse Event Reporting System (2015-2022) were analyzed. Four disproportionality methods were used to detect safety signals: reporting odds ratio (ROR), proportional reporting ratio, Bayesian Confidence Neural Network Propagation, and Multi-Item Gamma Poisson Shrinker. Venn analysis was used to compare and select common and specific AEs. RESULTS: This study included 73,042 patients treated with palbociclib, 25,142 with ribociclib, and 7563 with abemaciclib. All three inhibitors had 27 common AEs. Palbociclib exhibited the highest ROR for hematologic toxicities, while ribociclib showed the highest ROR for macrocytosis, nail disorders, and hepatic lesions. Abemaciclib displayed the highest ROR for mucosal toxicity. Common signals for both palbociclib and ribociclib included hematologic toxicities, decreased immune responsiveness, and aphthous ulcers. Myelosuppression, oral pain, and pseudocirrhosis were common signals for palbociclib and abemaciclib. Anemia, hepatotoxicity, and pneumonitis were observed as common signals for ribociclib and abemaciclib. Furthermore, specific AEs associated with palbociclib included fatigue, alopecia, and stomatitis. For ribociclib, specific AEs included electrocardiogram QT prolongation, thrombocytopenia, and decreased hemoglobin. Abemaciclib was specifically linked to diarrhea, vomiting, and interstitial lung disease. CONCLUSION: Our analysis revealed that palbociclib showed a higher risk of hematologic toxicity. Ribociclib showed higher risks of hepatotoxicity, nephrotoxicity, and QT prolongation. Abemaciclib showed higher risks of hepatotoxicity, gastrointestinal effects, interstitial lung disease, and thrombosis. These findings provide valuable insights for CDK4/6 inhibitor selection.
Sujet(s)
Systèmes de signalement des effets indésirables des médicaments , Aminopyridines , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Pharmacovigilance , Pipérazines , Inhibiteurs de protéines kinases , Purines , Pyridines , Food and Drug Administration (USA) , Humains , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , États-Unis/épidémiologie , Systèmes de signalement des effets indésirables des médicaments/statistiques et données numériques , Purines/effets indésirables , Inhibiteurs de protéines kinases/effets indésirables , Pipérazines/effets indésirables , Pipérazines/usage thérapeutique , Aminopyridines/effets indésirables , Pyridines/effets indésirables , Benzimidazoles/effets indésirables , Études cas-témoins , Antinéoplasiques/effets indésirables , FemelleRÉSUMÉ
Aim: Lysosomal pH changes are associated with drug resistance, cell growth and invasion of tumors, but effective and specific real-time monitoring of lysosomal pH compounds for cancer therapy is lacking. Materials & methods: Here, based on the covalent linkage of the anticancer drug palbociclib and fluorescent dye fluorescein isothiocyanate (FITC), we designed and developed a novel palbociclib-derived multifunctional molecule (Pal-FITC) for lysosomal targeting and diagnostic therapeutic integration. Results & discussion: Pal-FITC fluoresces is 20-fold stronger than that of FITC and shows a linear response in the pH range of 4.0-8.2 (R2 = 0.9901). Pal-FITC blocks cells in G1 phase via Cyclin D-CDK4/6-Rb. Conclusion: Our study provides new strategies for tumor-targeted imaging and personalized therapy.
Based on the covalent linkage of the anticancer drug and the fluorescent dye, we designed and developed a novel palbociclib-derived multifunctional molecule (Pal-FITC) for lysosomal targeting and diagnostic therapeutic integration. Pal-FITC responded linearly in the pH range of 4.08.2. In addition, Pal-FITC was able to effectively treat lung cancer without toxic side effects on normal cells. It has a significant cell cycle blocking phenomenon and blocks G1 phase cells via Cyclin D-CDK4/6-Rb. Our study provides a new strategy for tumor-targeted imaging and personalized therapy.
Sujet(s)
Antinéoplasiques , Lysosomes , Pipérazines , Pyridines , Humains , Pyridines/composition chimique , Pyridines/pharmacologie , Lysosomes/métabolisme , Pipérazines/composition chimique , Pipérazines/pharmacologie , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Colorants fluorescents/composition chimique , Colorants fluorescents/pharmacologie , Colorants fluorescents/synthèse chimique , Fluorescéine-5-isothiocyanate/composition chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Concentration en ions d'hydrogène , Lignée cellulaire tumorale , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Structure moléculaireRÉSUMÉ
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
Sujet(s)
Aminopyridines , Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Pipérazines , Inhibiteurs de protéines kinases , Purines , Pyridines , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Femelle , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Adulte d'âge moyen , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Pyridines/usage thérapeutique , Études rétrospectives , Sujet âgé , Pipérazines/usage thérapeutique , Aminopyridines/usage thérapeutique , Purines/usage thérapeutique , Taïwan , Inhibiteurs de protéines kinases/usage thérapeutique , Récidive tumorale locale/traitement médicamenteux , Adulte , Récepteurs des oestrogènes/métabolisme , Récepteurs à la progestérone/métabolisme , Résultat thérapeutique , Métastase tumorale , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , AsiatiquesSujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Inhibiteurs de protéines kinases , Humains , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Tumeurs du sein/traitement médicamenteux , Femelle , Inhibiteurs de protéines kinases/usage thérapeutique , Antinéoplasiques/usage thérapeutique , Thérapie moléculaire cibléeRÉSUMÉ
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
Sujet(s)
Biodisponibilité , Kinase-6 cycline-dépendante , Flavanones , Inhibiteurs de protéines kinases , Animaux , Humains , Rats , Administration par voie orale , Aminopyridines/pharmacocinétique , Aminopyridines/pharmacologie , Aminopyridines/administration et posologie , Glycoprotéine P/métabolisme , Glycoprotéine P/antagonistes et inhibiteurs , /pharmacologie , Cellules Caco-2 , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Cytochrome P-450 CYP3A/métabolisme , Inhibiteurs des enzymes du cytochrome P-450/pharmacologie , Inhibiteurs des enzymes du cytochrome P-450/administration et posologie , Flavanones/administration et posologie , Flavanones/pharmacologie , Simulation de docking moléculaire , Perméabilité , Pipérazines/pharmacocinétique , Pipérazines/pharmacologie , Pipérazines/administration et posologie , Inhibiteurs de protéines kinases/administration et posologie , Inhibiteurs de protéines kinases/pharmacocinétique , Purines/pharmacocinétique , Purines/administration et posologie , Purines/pharmacologie , Pyridines/pharmacocinétique , Pyridines/pharmacologie , Pyridines/administration et posologie , Rat Sprague-DawleySujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Inhibiteurs de protéines kinases , Récepteur ErbB-2 , Récepteurs des oestrogènes , Humains , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/mortalité , Tumeurs du sein/anatomopathologie , Femelle , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Récepteur ErbB-2/métabolisme , Récepteur ErbB-2/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/usage thérapeutique , Récepteurs des oestrogènes/métabolisme , Récepteurs à la progestérone/métabolisme , Adulte d'âge moyen , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Sujet âgéRÉSUMÉ
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Résistance aux médicaments antinéoplasiques , Facteur de transcription associé à la microphtalmie , N-acetylglucosaminyltransferase , Pipérazines , Pyridines , Humains , Kinase-4 cycline-dépendante/métabolisme , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Tumeurs du sein/métabolisme , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/génétique , Tumeurs du sein/anatomopathologie , Kinase-6 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Facteur de transcription associé à la microphtalmie/métabolisme , Facteur de transcription associé à la microphtalmie/génétique , Femelle , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Pipérazines/pharmacologie , Pyridines/pharmacologie , Lignée cellulaire tumorale , N-acetylglucosaminyltransferase/métabolisme , N-acetylglucosaminyltransferase/antagonistes et inhibiteurs , N-acetylglucosaminyltransferase/génétique , Animaux , Souris , Inhibiteurs de protéines kinases/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
The aim of this study is to share real-life data on the increase in creatinine due to CDK 4/6 inhibitor treatment and patients diagnosed with HR+/HER2-MBC and treated with ribociclib or palbociclib combined with ET were included in the study. While creatinine increase was observed in 17.9% (n = 19) of the 106 patients in the study population, 8.5% (n = 9) had Grade 1, 8.5% (n = 8) had Grade 2, and % 0.9 (n = 1) had Grade 3 creatinine elevation. The increase in creatinine occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine. Of the patients with high creatinine levels, 36.8% (n = 7) were over 65 years of age. Those with multiple comorbidities, blood urea nitrogen (BUN) >13.5 mg/dl, creatinine >0.66 mg/dl, BUN/creatinine ratio >19.95, glomerular filtration rate (GFR) >96.05 ml/min, and uric acid >4.69mg/dl. It was observed that the increase in the creatinine level was statistically significant (p <0.001). In conclusion, this study revealed that the increase in the serum creatinine secondary to ribociclib and palbociclib treatments is associated with kidney function tests and the number of concomitant diseases. Key Words: CDK 4/6 inhibitor, Creatinine elevation, Palbociclib, Ribociclib.
Sujet(s)
Aminopyridines , Créatinine , Kinase-4 cycline-dépendante , Pipérazines , Purines , Pyridines , Humains , Purines/effets indésirables , Purines/administration et posologie , Purines/usage thérapeutique , Créatinine/sang , Pipérazines/effets indésirables , Pipérazines/administration et posologie , Pipérazines/usage thérapeutique , Aminopyridines/effets indésirables , Aminopyridines/administration et posologie , Aminopyridines/usage thérapeutique , Femelle , Pyridines/effets indésirables , Pyridines/administration et posologie , Adulte d'âge moyen , Sujet âgé , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Tumeurs du sein/traitement médicamenteux , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Adulte , Inhibiteurs de protéines kinases/effets indésirables , Inhibiteurs de protéines kinases/administration et posologie , MâleRÉSUMÉ
CDK4/6 inhibitors are oral agents inhibiting key molecules of the cell cycle regulation. In patients with endocrine receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer, the combination of CDK4/6 inhibitors with endocrine therapy is an effective treatment in the metastatic setting. Now, two studies in the adjuvant setting - MonarchE (2 years of abemaciclib) and NATALEE (3 years of ribociclib) - report positive invasive disease-free survival. Here, we re-evaluate these seminal trials. First, an excess drop-out or loss-to-follow up occurred early in the control arms of both studies. Since both trials are open-label, there is concern that the patients who drop-out do not do so at random but based on socioeconomic factors and alternative options. Is it possible that the results merely appear favorable due to loss to follow up? Based on re-constructed Kaplan-Meier curves, we concluded the results of these studies remain fragile, being prone to informative censoring. Secondly, adverse events were notably higher in both trials, and some of them, like COVID-19 related deaths in NATALEE, raise serious concerns. Third, the potential costs associated with CDK4/6 inhibition given as adjuvant therapy are unprecedented. The NATALEE strategy, in particular, could affect up to 35 % of patients with newly diagnosed breast cancer, which is the cancer with the highest incidence worldwide. Without confirmatory data based on a placebo-controlled trial, or better identification of patients that would benefit from the addition of CDK4/6 inhibitors in the adjuvant setting, we argue against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Inhibiteurs de protéines kinases , Femelle , Humains , Aminopyridines/usage thérapeutique , Aminopyridines/effets indésirables , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/effets indésirables , Benzimidazoles/usage thérapeutique , Benzimidazoles/effets indésirables , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Traitement médicamenteux adjuvant , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/effets indésirables , Purines/usage thérapeutique , Purines/effets indésirables , Essais contrôlés randomisés comme sujetRÉSUMÉ
BACKGROUND: The current study evaluated the disease burden, health care resource utilization and analyzed the cost burden due to events of special interest among patients with breast cancer (BC) diagnosed and treated in Dubai, United Arab Emirates (UAE), in general and in the subset of patients treated with cyclin-dependent kinase (CDK) 4/6 inhibitors. METHODS: This retrospective cohort study, using insurance e-claims data from Dubai Real-World Database, was conducted from 01 January 2014 to 30 September 2021. Female patients aged ≥ 18 years with at least 1 diagnosis claim for BC and with continuous enrollment during the index period were included. RESULTS: Overall, 8,031 patients were diagnosed with BC (median age: 49.0 years), with the majority (68.1%) being in 41-60-year age group. During the post-index period, BC-specific costs contributed to 84% of the overall disease burden among patients with BC. Inpatient costs (USD 16,956.2) and medication costs (USD 10,251.3) contributed significantly to BC-specific costs. In the subgroup of patients in whom CDK4/6 inhibitors were part of the treatment regimen (n = 174), CDK4/6 inhibitors were commonly prescribed in combination with aromatase inhibitors (41.4%) and estrogen receptor antagonists (17.9%). In patients with BC, health care costs due to events of special interest (n = 1,843) contributed to 17% of the overall disease cost burden. CONCLUSION: The study highlights the significant cost burden among patients with BC, with BC-specific costs contributing to 84% of the overall disease cost burden. Despite few limitations such as study population predominantly comprising of privately insured expatriate patients and only direct healthcare costs being assessed in the current study, most indicative costs have been captured in the study, by careful patient selection and cost comparisons, as applicable. The findings can guide key health care stakeholders (payers and providers) on future policy measures aiming to reduce the cost burden among patients with BC.
Sujet(s)
Tumeurs du sein , Coûts indirects de la maladie , Humains , Femelle , Tumeurs du sein/thérapie , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/économie , Émirats arabes unis , Études rétrospectives , Adulte d'âge moyen , Adulte , Coûts des soins de santé/statistiques et données numériques , Sujet âgé , Acceptation des soins par les patients/statistiques et données numériques , Ressources en santé/statistiques et données numériques , Ressources en santé/économie , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Jeune adulteRÉSUMÉ
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors.
Sujet(s)
Aminopyridines , Benzimidazoles , Désipramine , Synergie des médicaments , Tests d'activité antitumorale sur modèle de xénogreffe , Humains , Benzimidazoles/pharmacologie , Benzimidazoles/administration et posologie , Aminopyridines/pharmacologie , Aminopyridines/administration et posologie , Animaux , Souris , Désipramine/pharmacologie , Lignée cellulaire tumorale , Protocoles de polychimiothérapie antinéoplasique/pharmacologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Femelle , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Prolifération cellulaire/effets des médicaments et des substances chimiques , Souris nude , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/métabolisme , Cellules MCF-7 , Cellules HCT116 , Antinéoplasiques/pharmacologie , Antinéoplasiques/usage thérapeutique , Antinéoplasiques/administration et posologie , Souris de lignée BALB CRÉSUMÉ
The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33â ±â 0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, Pâ =â .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.
Sujet(s)
Tumeurs du sein , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Récepteur ErbB-2 , Humains , Femelle , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/mortalité , Récepteur ErbB-2/métabolisme , Récepteur ErbB-2/antagonistes et inhibiteurs , Études rétrospectives , Adulte d'âge moyen , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Sujet âgé , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacologie , Adulte , Survie sans progression , Récepteurs des oestrogènes/métabolismeRÉSUMÉ
BACKGROUND: Current standard treatment for metastatic breast cancer (MBC) involves cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with endocrine therapy, showing potential in enhancing anti-tumor immune responses. CASE REPORT: This report details a clinical case of MBC where palbociclib was co-administered with letrozole. The integration of allogeneic tumor vaccination to this treatment led to heightened interferon-γ production, expansion of CD8+ and NK cell populations, and positive delayed-type hypersensitivity reactions, indicating successful development of anti-tumor immunity. The induced production of interferon-γ by tumor vaccination was associated with manageable modulation of sensitivity to palbociclib-letrozole therapy. Administration of the BioNTech/Pfizer Covid-19 vaccine compromised the anti-tumor immune response by reducing cytotoxic cell populations and increasing immunosuppressive cytokine production. The patient undergoing combined treatment achieved a progressive-free survival of 42 months. CONCLUSION: Incorporating active tumor vaccination with CDK4/6 inhibitor therapy presents a feasible approach for metastatic breast cancer. The precise regulation of the microenvironment emerges as a crucial factor and warrants careful consideration.
Sujet(s)
Protocoles de polychimiothérapie antinéoplasique , Tumeurs du sein , Vaccins anticancéreux , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Pipérazines , Pyridines , Humains , Femelle , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/immunologie , Pipérazines/administration et posologie , Pipérazines/usage thérapeutique , Pyridines/administration et posologie , Pyridines/usage thérapeutique , Vaccins anticancéreux/administration et posologie , Vaccins anticancéreux/immunologie , Vaccins anticancéreux/usage thérapeutique , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Létrozole/administration et posologie , Vaccins contre la COVID-19/administration et posologie , Vaccins contre la COVID-19/immunologie , Inhibiteurs de protéines kinases/usage thérapeutique , Inhibiteurs de protéines kinases/administration et posologie , Adulte d'âge moyen , Interféron gamma/métabolismeRÉSUMÉ
In search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH3 as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH3 co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSOd6 or its mixture with D2O using 1H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers.
Sujet(s)
Antinéoplasiques , Cycline D1 , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Transition épithélio-mésenchymateuse , Facteur de transcription STAT-3 , Tumeurs du sein triple-négatives , Humains , Tumeurs du sein triple-négatives/traitement médicamenteux , Tumeurs du sein triple-négatives/anatomopathologie , Tumeurs du sein triple-négatives/métabolisme , Facteur de transcription STAT-3/métabolisme , Facteur de transcription STAT-3/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Cycline D1/métabolisme , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Antinéoplasiques/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/synthèse chimique , Protéines proto-oncogènes c-myc/métabolisme , Femelle , Complexes de coordination/pharmacologie , Complexes de coordination/composition chimique , Complexes de coordination/synthèse chimique , Ligands , Carcinogenèse/effets des médicaments et des substances chimiques , Prolifération cellulaire/effets des médicaments et des substances chimiques , Platine/composition chimique , Platine/pharmacologie , Composés organiques du platine/pharmacologie , Composés organiques du platine/composition chimique , Composés organiques du platine/synthèse chimiqueRÉSUMÉ
The comprehensive genomic analysis of the head and neck squamous cell carcinoma (HNSCC) oncogenome revealed the frequent loss of p16INK4A (CDKN2A) and amplification of cyclin D1 genes in most human papillomavirus-negative HNSCC lesions. However, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown modest effects in the clinic. The aberrant activation of the PI3K/mTOR pathway is highly prevalent in HNSCC, and recent clinical trials have shown promising clinical efficacy of mTOR inhibitors (mTORi) in the neoadjuvant and adjuvant settings but not in patients with advanced HNSCC. By implementing a kinome-wide CRISPR/Cas9 screen, we identified cell-cycle inhibition as a synthetic lethal target for mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergism in HNSCC-derived cells in vitro and in vivo. Remarkably, we found that an adaptive increase in cyclin E1 (CCNE1) expression upon palbociclib treatment underlies the rapid acquired resistance to this CDK4/6 inhibitor. Mechanistically, mTORi inhibits the formation of eIF4G-CCNE1 mRNA complexes, with the consequent reduction in mRNA translation and CCNE1 protein expression. Our findings suggest that mTORi reverts the adaptive resistance to palbociclib. This provides a multimodal therapeutic option for HNSCC by cotargeting mTOR and CDK4/6, which in turn may halt the emergence of palbociclib resistance. SIGNIFICANCE: A kinome-wide CRISPR/Cas9 screen identified cell-cycle inhibition as a synthetic lethal target of mTORis. A combination of mTORi and palbociclib, a CDK4/6-specific inhibitor, showed strong synergistic effects in HNSCC. Mechanistically, mTORis inhibited palbociclib-induced increase in CCNE1.
Sujet(s)
Systèmes CRISPR-Cas , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Résistance aux médicaments antinéoplasiques , Tumeurs de la tête et du cou , Pipérazines , Pyridines , Carcinome épidermoïde de la tête et du cou , Humains , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/génétique , Kinase-4 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/génétique , Kinase-6 cycline-dépendante/métabolisme , Carcinome épidermoïde de la tête et du cou/génétique , Carcinome épidermoïde de la tête et du cou/traitement médicamenteux , Carcinome épidermoïde de la tête et du cou/métabolisme , Carcinome épidermoïde de la tête et du cou/anatomopathologie , Pipérazines/pharmacologie , Pipérazines/usage thérapeutique , Pyridines/pharmacologie , Souris , Animaux , Résistance aux médicaments antinéoplasiques/génétique , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Tumeurs de la tête et du cou/génétique , Tumeurs de la tête et du cou/traitement médicamenteux , Tumeurs de la tête et du cou/anatomopathologie , Tumeurs de la tête et du cou/métabolisme , Lignée cellulaire tumorale , Inhibiteurs de mTOR/pharmacologie , Inhibiteurs de mTOR/usage thérapeutique , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/usage thérapeutique , Sérine-thréonine kinases TOR/métabolisme , Cycline E/génétique , Cycline E/métabolisme , Tests d'activité antitumorale sur modèle de xénogreffe , Mutations synthétiques létales , Protéines oncogènesRÉSUMÉ
Breast cancer (BC) cells have a high risk of metastasis due to epithelial-mesenchymal transition (EMT). Palbociclib (CDK4/6 inhibitor) is an approved drug for BC treatment. However, the drug resistance and metastasis can impair the treatment outcome of Palbociclib. Understanding the mechanisms of EMT and Palbociclib drug resistance in BC is conducive to the formulation of novel therapeutic strategy. Here, we investigated the role of circHIAT1/miR-19a-3p/CADM2 axis in modulating EMT and Palbociclib resistance in BC. circHIAT1 and CADM2 were down-regulated in BC tissues and cell lines, and miR-19a-3p showed an up-regulation. circHIAT1 could interact with miR-19a-3p and suppress its activity, while miR-19a-3p functioned to negatively regulate CADM2. Forced over-expression of circHIAT1 could impaired the EMT status and migratory ability of BC cells, and this effect was inhibited by miR-19a-3p mimic. In addition, we also generated Palbociclib resistant BC cells, and showed that circHIAT1 and CADM2 were down-regulated in the resistant BC cells while miR-19a-3p showed an up-regulation. Forced circHIAT1 over-expression re-sensitized BC cells to Palbociclib treatment. Quercetin, a bioactive flavonoid, could suppressed the migration and invasion of BC cells, and re-sensitized BC cells to Palbociclib. The anti-cancer effect of quercetin could be attributed to its regulatory effect on circHIAT1/miR-19a-3p/CADM2 axis. In vivo tumorigenesis experiment further revealed that quercetin administration enhanced the anti-cancer effect of Palbociclib, an effect was dependent on the up-regulation of circHIAT1 by quercetin. In summary, this study identified quercetin as a potential anti-cancer compound to reverse Palbociclib resistance and impair EMT in BC cells by targeting circHIAT1/miR-19a-3p/CADM2 axis.
Sujet(s)
Tumeurs du sein , Kinase-6 cycline-dépendante , Résistance aux médicaments antinéoplasiques , Transition épithélio-mésenchymateuse , microARN , Pipérazines , Pyridines , Quercétine , Transition épithélio-mésenchymateuse/effets des médicaments et des substances chimiques , Humains , microARN/génétique , microARN/métabolisme , Tumeurs du sein/traitement médicamenteux , Tumeurs du sein/anatomopathologie , Tumeurs du sein/génétique , Tumeurs du sein/métabolisme , Femelle , Résistance aux médicaments antinéoplasiques/effets des médicaments et des substances chimiques , Pyridines/pharmacologie , Pipérazines/pharmacologie , Lignée cellulaire tumorale , Quercétine/pharmacologie , Animaux , Souris , Kinase-6 cycline-dépendante/métabolisme , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/génétique , Régulation de l'expression des gènes tumoraux/effets des médicaments et des substances chimiques , Kinase-4 cycline-dépendante/métabolisme , Kinase-4 cycline-dépendante/génétique , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Mouvement cellulaire/effets des médicaments et des substances chimiques , ARN long non codant/génétique , ARN long non codant/métabolisme , Souris nude , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
INTRODUCTION: Cyclin-dependent protein kinase 4/6 (CDK4/6) is a class of serine/threonine protein kinases that plays a key role in the regulation of the cell cycle. CDK4/6 is highly expressed in cancers such as breast cancer, melanoma, and non-small cell lung cancer (NSCLC). Currently, a variety of CDK4/6 inhibitors have been developed, aiming to develop effective inhibitors to solve CDK4/6 resistance and toxicity. AREAS COVERED: This article searches patents through Espacenet and reviews the development of widely studied CDK inhibitors and FDA-approved CDK4/6 inhibitors, as well as the latest progress of patented inhibitors with good inhibitory activity against CDK4/6 from 2020 to now. EXPERT OPINION: CDK4/6 is highly expressed in many tumors and has become an important anti-tumor target. Among the patents from 2020 to the present, many inhibitors have good kinase inhibitory effects on CDK4/6 and also show great development potential in anti-tumor. However, there is still an urgent need to develop novel CDK4/6 inhibitors that address challenges such as drug resistance, toxicity, and selectivity.
Sujet(s)
Antinéoplasiques , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Développement de médicament , Résistance aux médicaments antinéoplasiques , Tumeurs , Brevets comme sujet , Inhibiteurs de protéines kinases , Humains , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/pharmacologie , Tumeurs/traitement médicamenteux , Tumeurs/anatomopathologie , Antinéoplasiques/pharmacologie , AnimauxRÉSUMÉ
The synthesis, biochemical evaluation and radiosynthesis of a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and radioligand was performed. NT431, a newly synthesized 4-fluorobenzyl-abemaciclib, exhibited high potency to CDK4/6 and against four cancer cell lines with IC50 similar to that of the parent abemaciclib. We performed a two-step one-pot radiosynthesis to produce [18F]NT431 with good radiochemical yield (9.6 ± 3%, n = 3, decay uncorrected), high radiochemical purity (>95%), and high molar activity (>370 GBq/µmol (>10.0 Ci/µmol). In vitro autoradiography confirmed the specific binding of [18F]NT431 to CDK4/6 in brain tissues. Dynamic PET imaging supports that both [18F]NT431 and the parent abemaciclib crossed the BBB albeit with modest brain uptake. Therefore, we conclude that it is unlikely that NT431 or abemaciclib (FDA approved drug) can accumulate in the brain in sufficient concentrations to be potentially effective against breast cancer brain metastases or brain cancers. However, despite the modest BBB penetration, [18F]NT431 represents an important step towards the development and evaluation of a new generation of CDK4/6 inhibitors with superior BBB penetration for the treatment and visualization of CDK4/6 positive tumors in the CNS. Also, [18F]NT431 may have potential application in peripheral tumors such as breast cancer and other CDK4/6 positive tumors.
Sujet(s)
Aminopyridines , Benzimidazoles , Tumeurs du cerveau , Kinase-4 cycline-dépendante , Kinase-6 cycline-dépendante , Tomographie par émission de positons , Inhibiteurs de protéines kinases , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/métabolisme , Humains , Tomographie par émission de positons/méthodes , Tumeurs du cerveau/imagerie diagnostique , Tumeurs du cerveau/traitement médicamenteux , Tumeurs du cerveau/métabolisme , Tumeurs du cerveau/enzymologie , Kinase-6 cycline-dépendante/antagonistes et inhibiteurs , Kinase-6 cycline-dépendante/métabolisme , Lignée cellulaire tumorale , Benzimidazoles/pharmacologie , Benzimidazoles/composition chimique , Aminopyridines/composition chimique , Aminopyridines/pharmacologie , Inhibiteurs de protéines kinases/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/synthèse chimique , Animaux , Radiopharmaceutiques/composition chimique , Radio-isotopes du fluor/composition chimique , Encéphale/imagerie diagnostique , Encéphale/métabolisme , Souris , FemelleRÉSUMÉ
Cell cycle regulation is largely abnormal in cancers. Molecular understanding and therapeutic targeting of the aberrant cell cycle are essential. Here, we identified that an underappreciated serine/threonine kinase, cyclin-dependent kinase-like 3 (CDKL3), crucially drives rapid cell cycle progression and cell growth in cancers. With regard to mechanism, CDKL3 localizes in the nucleus and associates with specific cyclin to directly phosphorylate retinoblastoma (Rb) for quiescence exit. In parallel, CDKL3 prevents the ubiquitin-proteasomal degradation of cyclin-dependent kinase 4 (CDK4) by direct phosphorylation on T172 to sustain G1 phase advancement. The crucial function of CDKL3 in cancers was demonstrated both in vitro and in vivo. We also designed, synthesized, and characterized a first-in-class CDKL3-specific inhibitor, HZ1. HZ1 exhibits greater potency than CDK4/6 inhibitor in pan-cancer treatment by causing cell cycle arrest and overcomes acquired resistance to CDK4/6 inhibitor. In particular, CDKL3 has significant clinical relevance in colon cancer, and the effectiveness of HZ1 was demonstrated by murine and patient-derived cancer models. Collectively, this work presents an integrated paradigm of cancer cell cycle regulation and suggests CDKL3 targeting as a feasible approach in cancer treatment.
Sujet(s)
Kinase-4 cycline-dépendante , Humains , Animaux , Souris , Kinase-4 cycline-dépendante/métabolisme , Kinase-4 cycline-dépendante/antagonistes et inhibiteurs , Kinase-4 cycline-dépendante/génétique , Protein-Serine-Threonine Kinases/métabolisme , Protein-Serine-Threonine Kinases/génétique , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Kinases cyclines-dépendantes/métabolisme , Kinases cyclines-dépendantes/antagonistes et inhibiteurs , Kinases cyclines-dépendantes/génétique , Lignée cellulaire tumorale , Phosphorylation , Inhibiteurs de protéines kinases/pharmacologie , Tumeurs du côlon/anatomopathologie , Tumeurs du côlon/métabolisme , Tumeurs du côlon/génétique , Tumeurs du côlon/traitement médicamenteux , Cycle cellulaireRÉSUMÉ
Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.